Gelatin capsules have been used in the formulation of pharmaceuticals and food products. Gelatin has good availability, low cost, and no toxicity. Gelatin, however, is soluble in acidic media and hence not stable in gastric fluid. A few examples of gelatin capsules are discussed below.
WO 2007/098612 A1 discloses gastric-resistant gelatin compositions for use in the preparation of dosage forms, comprising modified gelatin with additional functional groups such as carboxylate groups or acyl groups and further addition of sodium alginate and fatty acid derivatives. The modified gelatin is used in normal softgel and hard gelatin capsule production processes. However, the reaction rate and viscosity of the modified gelatin is not easy to control.
WO 2009/024376 discloses a microcapsule for immobilizing organic or inorganic solids, lipophilic compounds, lipids or microorganisms for use in food additives, or as dietary supplements based on a spherical matrix encapsulation using alginate as the substance. The capsule comprises additional adjuncts and stabilizers in the alginate matrix. The immobilized ingredients are released after ingestion of the capsule only after passing through the stomach into the duodenum, and are protected from the prior digestive effects of the stomach. The capsules of WO 2009/024376 are prepared by complex mixing and spray drying or formation of beadlets, with collection of the particles from a CaCl2 bath, followed by drying.
WO 2010/029433 discloses capsules comprising at least one oily phase that comprises a fatty acid oil mixture and at least one surfactant in an alginate capsule formulation. It is mentioned that other polymers, e.g. gelatin, might be present in the capsule shell. The shell of the capsules of WO 2010/029433 is thinner compared to gelatin capsules, thereby allowing a larger amount of material to be encapsulated. Furthermore, it is stated that alginate capsules may offer several benefits over gelatin capsules with regard to temperature and humidity stability, decrease in gastrointestinal reflux symptoms, as well as no need for testing for bovine spongiform encephalopathy (BSE). However, the production of the capsules of WO 2010/029433 is disadvantageous as inter alia it requires large amounts of water to wash the capsules, in order to remove the excess CaCl2.
WO 2007/075475 discloses a capsule where the shell contains a gastric resistant natural polymer, a film forming natural polymer and optionally a gelling agent, where the gastric resistant polymer is a polysaccharide, such as pectin and pectin like materials. The film forming composition can be used to prepare softgel and hard gelatin capsules, where the fill material can be a liquid, a semi-solid or a solid tablet. The gastric resistant shell formulation can be “gelled” with the addition of CaCl2 and MgCl2. When preparing the gelatin/pectin formulation, there is a substantial increase in viscosity of the shell formulation, especially after adding the Ca chloride (CaCl2) and Mg chloride (MgCl2). However, this increase in viscosity is a limiting factor in the production of softgel capsules and the formulation has to be diluted with more water in order to bring it back into a workable range. The addition of additional water decreases the oxygen barriers properties of the shell substantially and renders the shell more fragile during manufacturing. The excess of water has to be evaporated during the drying process; drying takes longer and the active ingredients in the fill formulation may be exposed for a longer period of time to the additional water that will migrate into the fill formulation.
JP58194810A2 describes a miniature capsule with a size smaller than 5 mm, composed of gelatin and a polyhydric alcohol, where the surface of the capsule is coated with a powder, such as CaCl2 and covered with another coat of methoxy pectin or sodium alginate. The powder reacts with the polysaccharide and renders it insoluble in acid media. The difficulty in this process is applying the powder uniformly over the surface of the miniature capsules and applying a water based coating to the surface. Since the second coat contains a very big amount of water to dissolve the pectin or alginate, the water will penetrate the gelatin shell and will affect is physical characteristics and protective properties, as well as require another process to dry the capsules.
EP 0 888 778 A1 describes a dosage form intended to deliver a drug in the colon, without disintegrating in the upper intestinal tract. The dosage form consists of a film around an existing product or a shell containing the active ingredients. The film formulation is based on the interaction of gelatin with a polysaccharide, in this case a pectin. The film is rendered insoluble in the upper intestinal tract, by reacting the pectin with calcium salts and cross-linking the gelatin component with strong aldehydes. Other polysaccharides are mentioned, including alginate. This formulation suggested in this particular application has extremely wide ranges for the pectin and the gelatin, ranging from 1 to 99% of the composition. Such ranges would not be useable in an industrial application. Furthermore the gelatin is cross linked optionally with strong aldehydes, including formaldehyde, in order to protect it from the upper intestinal tract enzyme, otherwise the gelatin will be degraded by proteolitic enzymes. It is known that cross-linking of gelatin with strong aldehydes causes the gelatin to become completely insoluble. The application of those aldehydes to the product, either in capsule form or as a coating presents several hazards to health.
JP 200919696 claims an enteric capsule comprising a film, wherein the film contains at least one kind selected from the group consisting of a water-soluble salt of alginic acid, gelatin, agar and curdlan. The film may further comprise at least one kind of gelling agent selected from the group consisting of gellan gum, carrageenan, pectin, xanthan gum, locust bean gum and tamarind seed gum, and additionally the film may further comprise a plasticizer. The capsule is prepared by dip coating to form a hard capsule. The film is said to comprise about 20-90% by weight of the alginate. However, according to the working examples alginate constitutes at least 50% by weight of the film and only hard capsules are prepared.
JP 1176369 discloses an enteric soft capsule prepared from sodium alginate having a viscosity of 50 to 400 cps (in 1% aqueous solution at 20° C.) with a soft capsule film base consisting of gelatin, preferably type B, and plasticizer as the main raw materials at 1 to 10% by weight with 100% by weight gelatin without using a bivalent cation for crosslinking and gelatinizing sodium alginate. However, this gelatin base is limited to the production of soft gels.
JP 2009185022 claims an enteric sustained-release soft capsule, wherein the soft capsule is formed by kneading gelatin, polyhydric alcohols as plasticizers, polysaccharides, alkali metal salts and water, wherein the polysaccharides are at least two kinds selected from carrageenan, agar, locus bean gum, guar gum, tamarind seed polysaccharide, pectin, xanthan gum, glucomannan, chitin, pullulan, alginic acid and alginic acid derivatives. The capsule comprises from 6-40% by weight of the at least two kinds of polysaccharide, wherein the alkali metal salt is preferably a calcium salt.
US 2007/098786 describes enteric valproic acid soft gelatin capsule, in which the fill material comprises valproic acid or divalproex sodium and, optionally, one or more excipients. The capsule shell is prepared from a mass comprising a film-forming polymer, an acid insoluble polymer, an aqueous solvent, and optionally a plasticizer. Suitable film-forming polymers include gelatin. Suitable acid-insoluble polymers include, e.g., acrylic-acid/methacrylic acid copolymers, alginic acid salts, etc. The acid-insoluble polymer is present in an amount from about 8% to about 20% by weight of the wet gel mass. The weight ratio of acid-insoluble polymer to film-forming polymer is from about 25% to about 50%. The aqueous solvent is water or an aqueous solution of alkalis. Suitable plasticizers include glycerin and triethylcitrate. A disadvantage is that enteric valproic acid soft gelatin capsules may be smaller in size than currently available enteric coated tablets.
The use and application of alginate in film-forming projects has not been widely explored. Reasons for this include the difficulty in finding a combination with other film-formers that can be applied in an industrial environment. The present disclosure provides for the use of alginates in film-forming applications and the conditions for their application.